Project Summary We have completed a phase I study of high-dose focal radiation (SBRT) in combination with high- dose IL-2 for patients with metastatic melanoma and renal cell carcinoma. This study demonstrated response rates of 66.6% with the combined approach that is well above reported response rates for IL-2 alone of 15%. Preliminary immunogenicity studies identified an effector memory population of T cells associated with clinical response in these patients. To validate these Phase I results, we will perform a randomized phase II clinical trial of high-dose IL-2 versus high-dose IL-2 in combination with focal SBRT in patients with metastatic melanoma. We hypothesize that SBRT administered in combination with IL-2 will generate more effective anti-tumor immune responses that will result in control of un-irradiated metastatic lesions when compared to patients receiving IL-2 alone in patients with metastatic melanoma. We propose that high-dose per fraction (10-15 Gy) focal radiation combined with IL-2 immunotherapy will enhance immune responses that target residual disease. We propose that the mechanism for this enhanced anti-tumor immune response associated with radiation is through release of tumor antigen and endogenous adjuvants as well as modulation of the local tumor environment. We propose the following are key components in control of non-targeted metastatic lesions in patients receiving SBRT and IL-2: 1) SBRT results in tumor breakdown providing a source of antigen for self-vaccination, 2) SBRT destruction of tumor metastasis will be associated with adjuvant release that will enhance anti-tumor immune responses, and 3) the combined approach will enhance systemic T-cell mediated effector responses against tumor associated antigen. To test our hypothesis we will in Aim1: Perform a randomized phase II clinical trial of high-dose IL-2 versus high-dose IL-2 in combination with focal SBRT in patients with metastatic melanoma; and in Aim2: Evaluate markers of tumor lysis, inflammation and immune activation in the blood of patients receiving combined modality therapy with SBRT and high-dose IL-2 therapy. This study tests a highly promising combination of radiation and immunotherapy for the treatment of melanoma that would represent a significant advance in radiation medicine and immunotherapy in patient treatment. Additionally it generates mechanistic data that addresses some of the open questions in radiation medicine, which can be used to direct future combined radiation and immunotherapy approaches for cancer treatment.